Alterations in glutamatergic neurotransmission have been observed in response to alcohol and in schizophrenia. It is unknown how alcohol use disorders affect the glutamatergic system in schizophrenia. It is also unknown whether a history of alcohol abuse or dependence has a long-term effect on glutamate in schizophrenia. Acamprosate, an anti-relapse medication, appears to act as a partial agonist at the glutamatergic NMDA receptor. This application proposes to examine differences in baseline CNS glutamate concentrations and in response to a two-week acamprosate challenge between people with schizophrenia and a history of alcohol abuse/dependence versus people with schizophrenia and no history of alcohol abuse/dependence. This work will be an initial step in evaluating the vulnerability to alcohol use disorders among people with schizophrenia, understanding long-term neurochemical changes in response to alcohol and potential reasons for relapse, and a test of acamprosate as a partial agonist. Brain glutamate concentrations will be measured, in vivo, using proton magnetic resonance spectroscopy (1H-MRS) in areas with strong evidence of pathology in schizophrenia: the bilateral anterior cingulate cortices and the bilateral dorsolateral prefrontal cortices. The PI holds a NARSAD Young Investigator Award to use 1H-MRS to evaluate glutamate concentrations at baseline and in response to two weeks of acamprosate in people with chronic schizophrenia. This SOAR proposal aims to expand this project to enroll additional subjects, determine alcohol use history, and support the PI in establishing a research niche in the field of alcohol misuse and serious mental illness. PUBLIC HEALTH RELEVANCE: This research will help to understand the long-term impact of previous alcohol use in schizophrenia and how that previous use may affect potential relapse and response to medications. Understanding this will assist in the development of treatments for alcohol misuse in people with schizophrenia. Better treatments for this group will have a significant impact on public health through decreasing hospital stays, increasing the odds of stable housing, and improving productivity.